A Critical Role for IL-17RB Signaling in HTLV-1 Tax-Induced NF-κB Activation and T-Cell Transformation

Human t-cell leukemia virus type 1 (htlv-1) infection is linked to the development of adult t-cell leukemia (atl) and the neuroinflammatory disease htlv-1 associated myelopathy/tropical spastic paraparesis (ham/tsp). the htlv-1 tax protein functions as a potent viral oncogene that constitutively activates the nf-κb transcription factor to transform t cells; however,the underlying mechanisms remain obscure. here,using next-generation rna sequencing we identified the il-25 receptor subunit il-17rb as an aberrantly overexpressed gene in htlv-1 immortalized t cells. tax induced the expression of il-17rb in an iκb kinase (ikk) and nf-κb-dependent manner. remarkably,tax activation of the canonical nf-κb pathway in t cells was critically dependent on il-17rb expression. il-17rb and il-25 were required for htlv-1-induced immortalization of primary t cells,and the constitutive nf-κb activation and survival of htlv-1 transformed t cells. il-9 was identified as an important downstream target gene of the il-17rb pathway that drives the proliferation of htlv-1 transformed cells. furthermore,il-17rb was overexpressed in leukemic cells from a subset of atl patients and also regulated nf-κb activation in some,but not all,tax-negative atl cell lines. together,our results support a model whereby tax instigates an il-17rb-nf-κb feed-forward autocrine loop that is obligatory for htlv-1 leukemogenesis. © 2014 lavorgna et al.